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Mechanisms and Potential Therapies for Acquired Resistance to Inhibitors Targeting the Raf or MEK Kinases in Cancer

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Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 1))

Abstract

Aberrant activation of the Ras/Raf/MEK/ERK signaling pathway often occurs in human cancer through the acquisition of oncogenic mutations in key pathway components. In particular, Ras mutations are found in about 20 % of human cancers, and B-Raf mutations occur in more than half of all melanomas. Thus, this pathway has become an attractive target for cancer therapies. Inhibitors targeting either the Raf or MEK kinases have shown initial success in treating cancers that depend on the Ras/Raf/MEK/ERK signaling pathway; unfortunately, resistance to the inhibitors eventually develops. For both sets of inhibitors, resistance most commonly occurs via reactivation of the Ras/Raf/MEK/ERK pathway or upregulated signaling from an alternate pathway, such as the PI3K/AKT pathway. Here, we discuss the mechanisms for acquired resistance to inhibitors targeting the Raf or MEK kinases and possible combination therapies to overcome or delay drug resistance.

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Abbreviations

ATP:

Adenosine-5′-triphosphate

AML:

Acute myeloid leukemia

CML:

Chronic myelogenous leukemia

ERK:

Extracellular regulated kinase

EGFR:

Epidermal growth factor receptor

FGFR3:

Fibroblast growth factor receptor 3

HGF:

Hepatocyte growth factor

IGF-1R:

Insulin-like growth factor 1 receptor

MEK:

MAP or ERK kinase

NSCLC:

Non-small-cell lung carcinoma

PDGFR-β:

Platelet-derived growth factor receptor-β

PI3K:

Phosphatidylinositide 3-kinase

PTEN:

Phosphatase and tensin homolog

RTK:

Receptor tyrosine kinase

SAHA:

Suberoylanilide hydroxamic acid

STAT3:

Signal transducer and activator of transcription 3

VEGFR:

Vascular endothelial growth factor receptor

References

  1. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773:1213–26.

    Article  PubMed  CAS  Google Scholar 

  2. Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61:3595–8.

    PubMed  CAS  Google Scholar 

  3. Rushworth LK, Hindley AD, O’Neill E, Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26:2262–72.

    Article  PubMed  CAS  Google Scholar 

  4. Ritt DA, Monson DM, Specht SI, Morrison DK. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol. 2010;30:806–19.

    Article  PubMed  CAS  Google Scholar 

  5. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005;17:215–24.

    Article  PubMed  CAS  Google Scholar 

  6. Dong C, Waters SB, Holt KH, Pessin JE. SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. J Biol Chem. 1996;271:6328–32.

    Article  Google Scholar 

  7. Roskoski R Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105–43.

    Article  PubMed  CAS  Google Scholar 

  8. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  PubMed  CAS  Google Scholar 

  9. Downward J, Targeting RAS. Signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22.

    Article  PubMed  CAS  Google Scholar 

  10. Roring M, Brummer T. Aberrant B-Raf signaling in human cancer: 10 years from bench to bedside. Crit Rev Oncog. 2012;17:97–121.

    Article  PubMed  Google Scholar 

  11. Maurer G, Tarkowski B, Baccarini M. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene. 2011;30:3477–88.

    Article  PubMed  CAS  Google Scholar 

  12. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.

    Article  PubMed  CAS  Google Scholar 

  13. Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Suppression of BRAF (V599E) in human melanoma abrogates transformation. Cancer Res. 2003;63:5198–202.

    PubMed  CAS  Google Scholar 

  14. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

    Article  PubMed  CAS  Google Scholar 

  15. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  PubMed  CAS  Google Scholar 

  16. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  PubMed  CAS  Google Scholar 

  17. Mangana J, Levesque MP, Karpova MB, Dummer R. Sorafenib in melanoma. Expert Opin Investig Drugs. 2012;21:557–68.

    Article  PubMed  CAS  Google Scholar 

  18. Strumberg D. Sorafenib for the treatment of renal cancer. Expert Opin Pharmacother. 2012;13:407–19.

    Article  PubMed  CAS  Google Scholar 

  19. Woo HY, Heo J. Sorafenib in liver cancer. Expert Opin Pharmacother. 2012;13:1059–67.

    Article  PubMed  CAS  Google Scholar 

  20. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 2008;105:3041–6.

    Article  PubMed  CAS  Google Scholar 

  21. Laquerre S, Arnone M, Moss K, Yang J, Fisher K, Kane-Carson LS, Smitheman K, Ward J, Heidrich B, Rheault T, Adjabeng G, Hornberger K, Stellwagen J, Waterson A, Han C, Mook RA, Uehling D, King AJ. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-Raf V600E mutation. Mol Cancer Ther. 2009;8:B88.

    Article  Google Scholar 

  22. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  PubMed  CAS  Google Scholar 

  23. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  PubMed  CAS  Google Scholar 

  24. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, O’Day SJ, Blackman SC, Curtis CM, Lebowitz P, Ma B, Ouellet D, Kefford RF. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–901.

    Article  PubMed  CAS  Google Scholar 

  25. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207–15.

    Article  PubMed  CAS  Google Scholar 

  26. Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, Wolchok JD, Solit DB, Rosen N, Abdel-Wahab O, Levine RL, Chapman PB. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med. 2012;367:2316–21.

    Article  PubMed  CAS  Google Scholar 

  27. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.

    Article  PubMed  CAS  Google Scholar 

  28. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.

    Article  PubMed  CAS  Google Scholar 

  29. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.

    Article  PubMed  CAS  Google Scholar 

  30. Dry JR, Pavey S, Pratilas CA, Harbron C, Runswick S, Hodgson D, Chresta C, McCormack R, Byrne N, Cockerill M, Graham A, Beran G, Cassidy A, Haggerty C, Brown H, Ellison G, Dering J, Taylor BS, Stark M, Bonazzi V, Ravishankar S, Packer L, Xing F, Solit DB, Finn RS, Rosen N, Hayward NK, French T, Smith PD. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 2010;70:2264–73.

    Article  PubMed  CAS  Google Scholar 

  31. Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008;68:9375–83.

    Article  PubMed  CAS  Google Scholar 

  32. Yeh JJ, Routh ED, Rubinas T, Peacock J, Martin TD, Shen XJ, Sandler RS, Kim HJ, Keku TO, Der CJ. KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Mol Cancer Ther. 2009;8:834–43.

    Article  PubMed  CAS  Google Scholar 

  33. Garon EB, Finn RS, Hosmer W, Dering J, Ginther C, Adhami S, Kamranpour N, Pitts S, Desai A, Elashoff D, French T, Smith P, Slamon DJ. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Ther. 2010;9:1985–94.

    Article  PubMed  CAS  Google Scholar 

  34. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358–62.

    Article  PubMed  CAS  Google Scholar 

  35. Jing J, Greshock J, Holbrook JD, Gilmartin A, Zhang X, McNeil E, Conway T, Moy C, Laquerre S, Bachman K, Wooster R, Degenhardt Y. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol Cancer Ther. 2012;11:720–9.

    Article  PubMed  CAS  Google Scholar 

  36. Tentler JJ, Nallapareddy S, Tan AC, Spreafico A, Pitts TM, Morelli MP, Selby HM, Kachaeva MI, Flanigan SA, Kulikowski GN, Leong S, Arcaroli JJ, Messersmith WA, Eckhardt SG. Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther. 2010;9:3351–62.

    Article  PubMed  CAS  Google Scholar 

  37. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, Bayani N, Wang NJ, Neve RM, Guan Y, Hu Z, Knight Z, Feiler HS, Gascard P, Parvin B, Spellman PT, Shokat KM, Wyrobek AJ, Bissell MJ, McCormick F, Kuo WL, Mills GB, Gray JW, Korn WM. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 2009;69:565–72.

    Article  PubMed  CAS  Google Scholar 

  38. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  PubMed  CAS  Google Scholar 

  39. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, O’Neil BH, Balsom S, Balint C, Liersemann R, Vasko VV, Bloomston M, Marsh W, Doyle LA, Ellison G, Grever M, Ringel MD, Villalona-Calero MA. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29:2357–63.

    Article  PubMed  CAS  Google Scholar 

  40. Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, Gilbert J, Mehra R, Moore DT, Sheikh A, Hoskins J, Hayward MC, Zhao N, O’Connor W, Weck KE, Cohen RB, Cohen EE. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res Official J Am Assoc Cancer Res. 2012;18:2056–65.

    Article  CAS  Google Scholar 

  41. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, Ganchev H, Pover G, Morris C, Tzekova V. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5:1630–6.

    Article  PubMed  Google Scholar 

  42. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, Tebbutt NC. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2011;30:1216–23.

    Article  PubMed  Google Scholar 

  43. Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, Desar IM, Timmer-Bonte JN, Eckhardt SG, Lewis KD, Brown KH, Cantarini MV, Morris C, George SM, Smith PD, van Herpen CM. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res Official J Am Assoc Cancer Res. 2010;16:1613–23.

    Article  CAS  Google Scholar 

  44. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, Dummer R. Phase II open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res Official J Am Assoc Cancer Res. 2011;18:555–67.

    Article  Google Scholar 

  45. Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, Vaughn CS, Lorusso PM, Cohen RB, Davies MA, Kim KB. Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer. 2012. doi:10.1002/cncr.27790.

  46. Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat Rev Drug Discov. 2011;10:811–2.

    Article  PubMed  CAS  Google Scholar 

  47. Gibbons DL, Pricl S, Kantarjian H, Cortes J, Quintas-Cardama A. The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm. Cancer. 2012;118:293–9.

    Article  PubMed  CAS  Google Scholar 

  48. Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, Affolter A, Nourry A, Niculescu-Duvaz D, Springer C, Marais R. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med. 2010;2:35ra41.

    Google Scholar 

  49. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.

    Article  PubMed  CAS  Google Scholar 

  50. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853–61.

    Article  PubMed  CAS  Google Scholar 

  51. Su F, Bradley WD, Wang Q, Yang H, Xu L, Higgins B, Kolinsky K, Packman K, Kim MJ, Trunzer K, Lee RJ, Schostack K, Carter J, Albert T, Germer S, Rosinski J, Martin M, Simcox ME, Lestini B, Heimbrook D, Bollag G. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 2012;72:969–78.

    Article  PubMed  CAS  Google Scholar 

  52. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012;11:909–20.

    Article  PubMed  CAS  Google Scholar 

  53. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D’Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683–95.

    Article  PubMed  CAS  Google Scholar 

  54. Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS ONE. 2011;6:e28973.

    Article  PubMed  CAS  Google Scholar 

  55. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, Buchanan S, Henry JR, Starling JJ, Peng SB. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem. 2012;287:28087–98.

    Article  PubMed  CAS  Google Scholar 

  56. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF (V600E). Nature. 2011;480:387–90.

    Article  PubMed  CAS  Google Scholar 

  57. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC, Ng C, Chodon T, Scolyer RA, Dahlman KB, Sosman JA, Kefford RF, Long GV, Nelson SF, Ribas A, Lo RS. Melanoma whole-exome sequencing identifies (V600E) B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nature Commun. 2012;3:724.

    Article  Google Scholar 

  58. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.

    Article  PubMed  CAS  Google Scholar 

  59. Gowrishankar K, Snoyman S, Pupo GM, Becker TM, Kefford RF, Rizos H. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J Invest Dermatol. 2012;132:1850–9.

    Article  PubMed  CAS  Google Scholar 

  60. Kaplan FM, Kugel CH, Dadpey N, Shao Y, Abel EV, Aplin AE. SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor. J Biol Chem. 2012;287:41797–807.

    Article  PubMed  CAS  Google Scholar 

  61. Shi H, Moriceau G, Kong X, Koya RC, Nazarian R, Pupo GM, Bacchiocchi A, Dahlman KB, Chmielowski B, Sosman JA, Halaban R, Kefford RF, Long GV, Ribas A, Lo RS. Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors. Cancer Discovery. 2012;2:414–24.

    Article  PubMed  CAS  Google Scholar 

  62. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA. 2009;106:20411–6.

    Article  PubMed  CAS  Google Scholar 

  63. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, Meyerson M, Garraway LA. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol Official J Am Soc Clin Oncol. 2011;29:3085–96.

    Article  CAS  Google Scholar 

  64. Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P, Zhang XD. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res Official J Am Assoc Cancer Res. 2011;17:721–30.

    Article  CAS  Google Scholar 

  65. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010;70:6670–81.

    Article  PubMed  CAS  Google Scholar 

  66. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750–60.

    Article  PubMed  CAS  Google Scholar 

  67. Shao Y, Aplin AE. BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma. Cell Death Differ. 2012;19:2029–39.

    Article  PubMed  CAS  Google Scholar 

  68. Shi H, Kong X, Ribas A, Lo RS. Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011;71:5067–74.

    Article  PubMed  CAS  Google Scholar 

  69. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Lee RJ, Nolop NB, Saltz L. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28 Suppl; abstr 3534.

    Google Scholar 

  70. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.

    Article  PubMed  CAS  Google Scholar 

  71. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.

    Article  PubMed  CAS  Google Scholar 

  72. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal. 2011;4:ra17.

    Google Scholar 

  73. Hatzivassiliou G, Liu B, O’Brien C, Spoerke JM, Hoeflich KP, Haverty PM, Soriano R, Forrest WF, Heldens S, Chen H, Toy K, Ha C, Zhou W, Song K, Friedman LS, Amler LC, Hampton GM, Moffat J, Belvin M, Lackner MR. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther. 2012;11:1143–54.

    Article  PubMed  CAS  Google Scholar 

  74. Wang H, Daouti S, Li WH, Wen Y, Rizzo C, Higgins B, Packman K, Rosen N, Boylan JF, Heimbrook D, Niu H. Identification of the MEK1 (F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res. 2011;71:5535–45.

    Article  PubMed  CAS  Google Scholar 

  75. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3:ra84.

    Google Scholar 

  76. Meng J, Peng H, Dai B, Guo W, Wang L, Ji L, Minna JD, Chresta CM, Smith PD, Fang B, Roth JA. High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). Cancer Biol Ther. 2009;8:2073–80.

    Article  PubMed  CAS  Google Scholar 

  77. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3 K signalling in colorectal cancer cell lines. Int J Cancer J Int du Cancer. 2009;125:2332–41.

    Article  CAS  Google Scholar 

  78. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C, Stegmeier F. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009;69:4286–93.

    Article  PubMed  CAS  Google Scholar 

  79. Yoon YK, Kim HP, Han SW, Oh do Y, Im SA, Bang YJ, Kim TY. KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: implication for combinatorial approach. Mol Carcinog. 2010;49:353–362.

    Google Scholar 

  80. Dai B, Meng J, Peyton M, Girard L, Bornmann WG, Ji L, Minna JD, Fang B, Roth JA. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17. Cancer Res. 2011;71:3658–68.

    Article  PubMed  CAS  Google Scholar 

  81. Gray-Schopfer VC, Karasarides M, Hayward R, Marais R. Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res. 2007;67:122–9.

    Article  PubMed  CAS  Google Scholar 

  82. Troiani T, Vecchione L, Martinelli E, Capasso A, Costantino S, Ciuffreda LP, Morgillo F, Vitagliano D, D’Aiuto E, De Palma R, Tejpar S, Van Cutsem E, De Lorenzi M, Caraglia M, Berrino L, Ciardiello F. Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells. Br J Cancer. 2012;106:1648–59.

    Article  PubMed  CAS  Google Scholar 

  83. Paraiso KH, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, Messina JL, Flaherty KT, Smalley KS. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102:1724–30.

    Article  PubMed  CAS  Google Scholar 

  84. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  PubMed  CAS  Google Scholar 

  85. Martinelli E, Troiani T, Morgillo F, Rodolico G, Vitagliano D, Morelli MP, Tuccillo C, Vecchione L, Capasso A, Orditura M, De Vita F, Eckhardt SG, Santoro M, Berrino L, Ciardiello F. Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells. Clinical Cancer Res Official J Am Assoc Cancer Res. 2010;16:4990–5001.

    Article  CAS  Google Scholar 

  86. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006;5:1136–44.

    Article  PubMed  CAS  Google Scholar 

  87. Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y, Ribas A, Lo RS, Weber JS, Sondak VK, John JK, Sarnaik AA, Koomen JM, Smalley KS. The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clinical Cancer Res Official J Am Assoc Cancer Res. 2012;18:2502–14.

    Article  CAS  Google Scholar 

  88. King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, Karreth F, Lougheed JC, Lee J, Chau D, Stout TJ, May EW, Rominger CM, Schaber MD, Luo L, Lakdawala AS, Adams JL, Contractor RG, Smalley KS, Herlyn M, Morrissey MM, Tuveson DA, Huang PS. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006;66:11100–5.

    Article  PubMed  CAS  Google Scholar 

  89. Shen M, Lyne P, Aquila B, Drew L. Linking molecular characteristics to the pharmacological response of a panel of cancer cell lines to the BRAF inhibitor, AZ628. 98th AACR Annual Meeting 2007; Los Angeles.

    Google Scholar 

  90. Amiri P, Aikawa M, Dove J, Stuart D, Poon D, Pick T, Ramurthy S, Subramanian S, Levine B, Costales A, Harris A, Paul R. CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits proliferation and survival of cancer cell lines with Ras/Raf pathway mutations. 97th AACR Annual Meeting 2006; Washington, DC.

    Google Scholar 

  91. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clinical Cancer Res Official J Am Assoc Cancer Res. 2007;13:1576–83.

    Article  CAS  Google Scholar 

  92. Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger CM, Erskine S, Fisher KE, Yang J, Zappacosta F, Annan R, Sutton D, Laquerre SG. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clinical Cancer Res Official J Am Assoc Cancer Res. 2011;17:989–1000.

    Article  CAS  Google Scholar 

  93. Daouti S, Wang H, Li WH, Higgins B, Kolinsky K, Packman K, Specian A Jr, Kong N, Huby N, Wen Y, Xiang Q, Podlaski FJ, He Y, Fotouhi N, Heimbrook D, Niu H. Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy. Cancer Res. 2009;69:1924–32.

    Article  PubMed  CAS  Google Scholar 

  94. Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA Jr, Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008;18:6501–4.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This project was supported by Federal funds from the National Cancer Institute.

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No potential conflicts of interest were disclosed.

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  1. Laboratory of Cell and Developmental Signaling, National Cancer Institute at Frederick, Frederick, MD, 21702, USA

    Alyson K. Freeman & Deborah K. Morrison

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Correspondence to Deborah K. Morrison .

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  1. Dept. Microbiology, Immunology &, Molecular Genetics, University of California, Los Angeles, Charles E. Young Dr. E. 609, Los Angeles, 90095, California, USA

    Benjamin Bonavida

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Freeman, A.K., Morrison, D.K. (2013). Mechanisms and Potential Therapies for Acquired Resistance to Inhibitors Targeting the Raf or MEK Kinases in Cancer. In: Bonavida, B. (eds) Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7070-0_3

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